Recent improvements in the design and facile operation of gas isotope ratio mass spectrometers (IRMS) and the sample inlets used to convert target biological analytes to the appropriate simple gases have increased sample throughput, increased analytical sensitivity for the stable isotopic species (13C, 15N, 18O, 2H, and potentially 34S), reduced or eliminated the time and labor-intensiveness of off-line sample preparation, reduced the amount of analyte material required for precise isotopic analysis, reduced the possibility of sample gas contamination with room air, and increased the number of target analytes that can be converted to the gas phase for isotopic analysis. These improvements will have a significant impact on the research capabilities of clinical investigators who examine substrate metabolism, endocrine actions, and metabolite production and clearance rates in normal and pathophysiologic conditions. These advances are especially important to investigators who need to determine very low stable isotopic abundances (e.g. less than 0.05 MPE) in nanogram quantities of analyte isolated from complex biological matrices such as urine, tissue, blood, and breath. These low enrichments of all isotopic species cannot be precisely detected by conventional gas chromatography-quadrupole-MS methods. As a result, many investigators are turning to IRMS to answer biological questions that previously could not be addressed. The improved IRMS are rapidly replacing the older, antiquated and less sensitive instruments. This SIG application describes the analytical and service problems associated with the existing IRMS. This application seeks to replace an existing IRMS that has analytical limitations, an inflexible data system, and increasing down time due to malfunctioning electrical components. We have assembled an excellent group of clinical investigators at Washington University Medical School and the University of Rochester with substantial analytical requirements for the precision and flexibility provided by a state-of-the art IRMS with multiple sample inlets. These investigators utilize IRMS to examine metabolic aspects associated with advancing age and physical frailty, cancer cachexia. the treatment of obesity, glucose counterregulatory mechanisms in diabetes, and muscle wasting and immune cell function in AIDS. The requested instrument will substantially augment the quality and quantity of the scientific observations that can be pursued with innovative mass spectrometric instrumentation.